The primary objectives of this research project is to develop methods for the design of ligands that bind strongly to receptors (enzymes, viral proteins, etc.) of known structure. This is a fundamental problem in the development of new drugs. Any contribution that can help in this area has widespread implications, although it is well known that the design of such ligands is a small step in the lengthy process of creating a viable drug. The strategy proposed for such rational ligand design has three parts. The first is to have an efficient method for the search of known binding sites (or more generally receptor surfaces) for positions that interact strongly with a range of functional groups. Second, given a set of such positions and orientations for functional groups, it is necessary to connect the functional group to form molecules that are candidates for synthesis. Finally, a method is needed to estimate which of these molecules is likely to have the strongest binding constants. Molecular mechanics and dynamics techniques are being implemented that permit an efficient search of the binding site using multiple copies of the functional groups. For connecting the functional groups to form molecules, two types of approaches are being developed. The first makes use of data bases and searches for hydrocarbon compound that have carbon hydrogen bonds appropriately oriented at the correct distance to link two or more functional groups, while simultaneously interacting with the protein through favorable van der Waals interactions. An alternative is based on a Monte Carlo algorithm and a pseudo-energy that creates molecular de novo by connecting carbon atoms with different valences to each other and to the functional groups. For evaluating the binding of the ligands, several methodologies will be used. Free energy simulations will be employed to compare similar proposed (or existing) ligands to gain insight into elements that are important. These results will be combined with a more general and less computer intensive approach based on empirical data and simplified representation of solvent effects. Series of closely related compounds for which x-ray structures and binding constants are available will be examined.